A vast majority of pharmaceutical agents (e.g., drugs) in clinical use today are given either orally or by injection. While injection provides a fast and direct route to the blood stream, injection often causes pain and anxiety and, occasionally, contamination. Further, injection does not provide for a constant or sustained delivery of drugs. Finally, when a drug is injected by a syringe, the entire dose is placed in the body and cannot be withdrawn should an adverse reaction occur.
Oral administration subjects the pharmaceutical agent to hepatic metabolism. Hepatic metabolism substantially degrades the effectiveness of pharmaceutical agents, up to 90 percent in some cases. More specifically, the first organ that receives an intestine absorbed drug taken orally is the liver. The liver detoxifies molecules that are foreign to the body. Most drug molecules are considered by the liver to be foreign. As a result, a significant quantity of a particular medicine may never reach the rest of the body due to the liver's detoxifying the drug's molecules. The degree of detoxification varies from person to person and may account for adverse reactions in some people and not others by influencing the amount of a drug that is left for absorption by the remainder of the body. More importantly, the decrease in effectiveness due to hepatic metabolism by the liver leads to increases in the amount of the agent being administered, which leads to undesirable side effects and gastric intolerance. That is, the amount taken by mouth is usually more than the body needs, often resulting in adverse side effects. Further, because dosage requirements often vary from individual to individual, it is difficult to tailor individual dosages using the predefined amounts determined by manufacturers of orally administered drugs. Finally, as with a syringe injection, when a drug is taken by mouth and absorbed, the entire dose is in the body. If an adverse reaction takes place it is difficult to remove the drug to stop the reaction. Nevertheless, oral administration presently is the most preferred way of giving pharmaceutical agents due to the ease of administration and avoidance of the need for invasive vascular access, as required by injections.
The adult skin structure can be broken into three layers. The stratum corneum, which is actually part of the epidermal layer, is the first layer of skin defense against the exterior environment. The stratum corneum is capable of absorbing superficial trauma while still maintaining adequate protection against loss of water and ingress of micro organisms and other substances. The stratum corneum layer is 15-20 cells thick. In many areas of the human body, the stratum corneum layer is very thin, often below several microns. The intercellular space of the stratum corneum is approximately 30 percent by volume. The intercellular space is filled by lipid composition, which is ideally suited to form a transport barrier. The inner layer of the stratum corneum is in contact with granular cells (very moist) and the outer layer is in contact with a dry environment. Thus a substantial water content gradient exists across the stratum corneum.
The second layer is the epidermal layer, which consists of epidermal cells bound together by tight junctions into a viscoelastic matrix. Between the junctions lie heavily convoluted lipid-filled extracellular spaces containing a host of cellular lymphocytic factors, enzymes and other anti-microbial agents. The epidermal layer is the body's prime protective barrier. Its basal cells provide metabolic and additional water barrier functions. The epidermal barrier provides a formidable defense structure even in the absence of the stratum corneum, especially to water-soluble agents that do not possess a lipid extracellular phase. Enzyme activity may be controlled or rendered inactive by employing chemical, enzymic or heat treatment.
The innermost layer is the dermal layer. The dermal layer consists of basal germ cells positioned upon a basal membrane with known permeability of approximately 40 kilodaltons and below. Unless specific excitation factors are present, large molecular weight materials cannot cross the basal membrane.
Below the basal membrane are the majority of the capillary loops that comprise the terminal states of the microcirculation tree (i.e., the blood vessels) of the human organisms. The capillary loops are the target of current passive transdermal drug delivery systems (described below). Because a very large number of capillary loops are present, large surface areas are available for the systemic exchange of fluids.
Penetrating all three skin layers are numerous hair follicles in various growth states--telogen, anagen and catagen. The hair follicle growth stage correlates with the depth of the follicle, late-anagen follicles being the deepest and closest to the most heavily developed capillary blood supply. The centerline of the hair follicle is positioned less than five microns from the encircling capillary blood supply. The stratum corneum follows the invagination of the follicles at the skin level, terminating approximately half-way down the follicles. The sensory nerve network that surrounds the follicles responds to any physical excitation on the hair shaft. Thus, a highly sensitive responsive system is present in the hair follicle regions of the skin. Follicle density on skin surfaces varies depending upon location from 100/cm.sup.2 to 900/cm.sup.2.
Other than by syringe, there are two methods by which drugs can be delivered through the skin--passive and active diffusion. Passive diffusion involves placing a concentration of drug in a reservoir on the surface of the skin and allowing the drug to passively diffuse through the skin into the body. Since there are natural barriers in the skin which keep almost all molecules from entering the body through the skin, only a few molecules from the reservoir of the drug pass through the skin and are absorbed first by the blood stream and then by the body.
Due to natural skin barriers, few pharmaceuticals have been successfully diffused through the skin and into the subdermal microcirculation regions of the human body, i.e., the underlying blood vessels. The most successful drugs to be diffused through the skin are clonidine, nitroglycerin, scopolamine, and estradiol. Because these drugs are effective at very low plasma concentrations, they can be applied using small passive skin patches. A 10 ng/ml plasma concentration has been arbitrarily adopted by the industry as a mean figure above which passive transdermal drug delivery is not effective. This concentration level eliminates the possibility of passive transdermal delivery of such highly successful agents as aspirin, which requires a concentration of 150,000 ng/ml to be effective. Currently, acetaminophen, cimetidine, and indomethacin cannot be delivered by passive transdermal drug delivery systems.
In addition to concentration level, molecular size is an issue with the passive diffusion of drug absorption. The skin's natural barriers limit or prevent absorption of medicaments that are composed of large molecules. Therefore, with passive diffusion, if a medicine is to be effective in the body, it must work well at very low dosages and be of a molecular size that the skin will allow to enter the body. While chemical enhancers have been investigated as solutions to allow for greater dosage absorption through the skin by passive diffusion, none have worked well enough to pass the Federal Drug Administration (FDA) requirements and/or be successful commercially.
A potentially more viable way for drugs to transcend the skin's barriers is to use an active energy source that "pushes" or "pulls" drug molecules through the skin and, at the same time controls, the rate of delivery. An energy driven system will allow a greater quantity of the medicine to be delivered in a shorter or variable time frame. Potentially an energy driven system will permit larger molecular weight drugs to transcend the barriers of the skin in a short time period.
Two types of active transdermal drug delivery have been proposed. The first, which is called iontophoresis, is a system that uses a direct current of electricity to charge drugs. Electrically charged drugs are driven into the skin. To date, there is only one medicine, Lidocaine, used in such a device. Lidocaine is a drug used for local anesthesia. Extensive investigation is presently being conducted by the pharmaceutical industry on the use of iontophoresis for drug delivery. While this method of delivery is slow, it probably will increase the number of medicaments used for transdermal drug delivery. Furthermore, delivery is better controlled, when compared to passive diffusion.
The other method of active drug delivery uses ultrasound as the energy source. For a variety of reasons, the results of drug delivery by this method have traditionally been inconsistent. Results of previous experiments have been difficult to repeat. More specifically, it has been known for several decades that ultrasound radiation pressure applied to drug molecules in contact with skin can increase transdermal penetration rate. The mechanism of action has been unclear with some researchers citing boundary stirring effect, some citing microchannel production via cavitation and others citing direct radiation pressure onto the drug, pumping it into the skin.
Some researchers have conducted studies of the interaction of ultrasound and specific drug formulations. Some researchers have applied an ultrasonic field to drug molecules themselves, rather than to the skin and associated structures. Other researchers have shown that ultrasound is effective in shearing polymeric compositions of drugs contained in transdermal patches. The intent of these researchers was to modulate the release rate of a drug from a polymeric matrix. Finally, some researchers have applied ultrasound to the skin itself. The following U.S. Pat. Nos. describe some of the results of the foregoing research: 4,657,543; 4,767,402; 4,780,212; 4,821,740; 4,948,587; 4,953,565; and 5,007,438. Also see Patent Cooperation Treaty (PCT) application No. 91/12772 and German Patent No. 27 56 460. Most, if not all, of the foregoing patents show a lack or no control of application direction, little or no control of frequency and power levels, no control of duty cycle and ignorance of a host of other controlling factors.
Various criteria for drug delivery enhancer design have been established. They are: (i) the enhancer should elicit no pharmacological response; (ii)the enhancer should be specific in its action; (iii)the enhancer should act immediately with a predictable duration and its action should be reversible; (iv)the enhancer should be chemically and physically stable, and be compatible with all of the components of the drug formulation; (v)the enhancer should be odorless, colorless, and tasteless; and (vi) the enhancer should be nontoxic, nonallergenic, and a nonirritant. These criteria can be conveniently applied with slight modification to all transdermal drug delivery enhancement approaches, both chemical and nonchemical. No single drug delivery enhancement approach available today meets all of the foregoing criteria. Organic enhancers produce a characteristic foul taste in the mouth shortly after skin application. Several alcohol or solvent-based enhancers cause severe skin irritation and can lead to an eczematous reaction. Device-based enhancers such as iontophoretic titrators come closer to satisfying all of the criteria, but fall short in broad spectrum general applicability, specificity of action, reversibility of action and nonirritability.
As will be better understood from the following discussion, the present invention is directed to providing an active transdermal drug delivery system that enhances the diffusion of large molecular weight substances (e.g., large molecular weight drugs) between an external device-based reservoir and the subdermal microcirculation tree of an organism, such as the human body. This result is achieved by using ultrasonic energy to excite the skin system of the organism in a way that allows multifrequency, multidirectional subsurface waves to diffuse large molecular weight substances through the skin in an efficient and controllable manner.